Unc-51-like kinase 1/2-mediated endocytic processes regulate filopodia extension and branching of sensory axons

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-04, Vol.104 (14), p.5842-5847
• Main Authors: Zhou, Xiang, Babu, J. Ramesh, da Silva, Susana, Shu, Qing, Graef, Isabella A, Oliver, Tim, Tomoda, Toshifumi, Tani, Tomomi, Wooten, Marie W, Wang, Fan
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Autophagy-Related Protein-1 Homolog; Axons; Axons - drug effects; Axons - physiology; Biological Sciences; Cell growth; Cell Line; Embryo, Mammalian; Endocytosis; Fluorescent Antibody Technique, Direct; Ganglia, Spinal - cytology; Ganglia, Spinal - enzymology; Green Fluorescent Proteins - metabolism; Growth cones; Growth Cones - enzymology; Growth Cones - physiology; Humans; Internalization; Kinases; Mice; Nerve Growth Factor - pharmacology; Neurites - physiology; Neurons; Neurons, Afferent - enzymology; Plasmids; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pseudopodia; Pseudopodia - physiology; Receptor Cross-Talk - drug effects; Receptor, trkA - metabolism; Receptors; RNA Interference; RNA, Small Interfering - metabolism; Sensory neurons; Studies; Transcription Factors - metabolism; Ubiquitin - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0701402104

The molecular mechanism and significance of endocytic processes involved in directional axon elongation are not well understood. The Unc-51 family of serine/threonine kinases was shown to be important for axon growth and was also linked to endocytosis, providing an entry point to study this problem. We found that mouse Unc-51-like kinase 1/2 (Ulk1/2) proteins are localized to vesicular structures in growth cones of mouse spinal sensory neurons. RNAi-mediated knockdown of Ulk1 and/or Ulk2 resulted in impaired endocytosis of nerve growth factor (NGF), excessive axon arborization, and severely stunted axon elongation. The evidence also indicates that Ulk1/2 mediates a non-clathrin-coated endocytosis in sensory growth cones. Interestingly, NGF can induce the interaction of Ulk1 with TrkA receptor complexes through promoting K63-polyubiquitination of Ulk1 and binding of Ulk1 to the scaffolding protein p62. These results and additional studies suggest that Ulk1/2 proteins regulate filopodia extension and neurite branching during sensory axon outgrowth, probably through regulating TrkA receptor trafficking and signaling.